HER2-low across solid tumours: different incidences and definitions

Area of Science:

• Oncology
• Pharmacology
• Diagnostic Pathology

Background:

• Antibody-drug conjugates like trastuzumab deruxtecan (T-DXd) are effective in HER2-positive and HER2-low solid tumors.
• T-DXd demonstrates improved survival in breast cancer and objective responses in HER2-low tumors across various cancers.
• Accurate identification of HER2 expression is critical for patient selection and treatment efficacy.

Purpose of the Study:

• To review HER2 protein expression and gene amplification in solid tumors where T-DXd shows potential.
• To assess the accuracy and limitations of HER2 testing methods, especially for HER2-low cancer detection.
• To highlight the need for standardized diagnostic criteria for T-DXd therapy in HER2-low tumors.

Main Methods:

• A semi-systematic literature search of EMBASE, Medline, Cochrane, and PubMed databases.
• Calculation of median incidences for HER2-positive, HER2-low, and HER2-0 by immunohistochemistry (IHC).
• Analysis of HER2 amplification by in situ hybridization (ISH) across 144 included studies.

Main Results:

• Median HER2-low incidences: 52% (breast), 16% (gastro-oesophageal), 58% (endometrial), 17% (ovarian).
• Unknown incidences for HER2-low in lung and cervical cancers.
• Factors affecting detection include tumor heterogeneity, antibody clones, observer variability, and lack of scoring criteria.

Conclusions:

• A significant proportion of patients with HER2-low tumors could benefit from T-DXd therapy.
• Limitations in current HER2 detection accuracy hinder the clinical utility of T-DXd for HER2-low cancers.
• Further research and standardization of diagnostic methods are essential to optimize T-DXd treatment.